Increasing evidence indicates that high serum insulin-like growth factor-1 (IGF-1) is associated with elevated risk of colorectal, breast, and endometrial cancer. Three Insulin Resistance Syndrome-related conditions, type 2 diabetes, obesity, and sedentary lifestyle, are also associated with greater risk of these cancers, and hyperinsulinemia is hypothesized to drive these relationships, at least in part. Insulin shares 40 percent homology with IGF-1, and biologic studies suggest both are mitogens. However, few epidemiologic studies have evaluated cancer risk based on insulin levels, and none have been prospective with sufficient sample size or adequate control for confounders. Similarly, there are sparse epidemiologic data regarding free IGF-1 and cancer, even though the unbound form is the main bioactive component. A cross-sectional study by our group found free IGF-I more strongly associated with breast cancer than total IGF-1. To provide definitive evidence of their associations with cancer, a prospective study of insulin and free IGF-1 is necessary. Therefore, the purpose of this application is to determine the effects of high serum insulin and free IGF-1 on risk of incident colorectal, breast and endometrial cancer in postmenopausal women. Specimens and data will be obtained from the Observational Study of the Women's Health Initiative (WHI), a large (n=93,725), ethnically and geographically diverse cohort of postmenopausal women aged 50-79. We propose conducting a case-cohort study, testing baseline serum for fasting glucose, insulin, total and free IGF-1, IGF binding protein-3 (IGFBP-3), and total estradiol. Follow-up will average 7 years, with cases excluded if diagnosed in the first 18 months. Our specific aims are to study: (1) The independent effects of high serum insulin and free IGF-1 on risk of colorectal (n=500), breast (n=900) and endometrial cancers (n=300); (2) Among the subcohort (controls; n=900), the factors related to levels of total IGF-1, free IGF-1, and IGFBP-3; (3) Whether type 2 diabetes is an independent risk factor for colorectal, breast and endometrial cancers, controlling for insulin resistance, IGF-1 and IGFBP-3.